Viral infections are controlled by immune responses associated with the induction of cellular immunity mediated by T lymphocytes, which kill virus-infected targets and control viral synthesis, and of humoral immunity mediated by B lymphocytes, which produce antibodies that inactivate viruses. The presence of long lasting antibody responses is important to maintain resistance to re- infection and is a goal of vaccine design. Studies on immune system activation and homeostasis have shown, however, that one should not think of immune responses to pathogens as isolated independent events, but instead as part of a continuum within an immune system modulated by memory lymphocyte pools specific to previously encountered pathogens. Prior T cell responses influence the nature of T cell responses to newly encountered pathogens, and newly encountered pathogens alter the homeostasis of memory T cell pools specific to previously encountered pathogens. This modulation of T cell responses can alter viral pathogenesis and is a component of what we refer to as heterologous immunity, but heterologous immunity has not been systematically investigated for B cell-dependent antibody responses. In fact, viral infections can enhance antibody responses to previously encountered viruses and sometimes to auto (self) antigens, including those associated with experimental autoimmune diseases like diabetes and lupus erythematosis. Our recent data have demonstrated profound influences in vivo of virus-specific CD4 T cells on B cells presenting viral antigens on their class II molecules, regardless of the B cell immunoglobulin receptor (BCR) specificity. Some of these B cells are lysed by CD4 T cells, whereas others are induced to polyclonally proliferate and differentiate. Here we propose to examine the phenomenon of BCR-independent polyclonal B cell activation and the influence of heterologous viral infections on the homeostasis of humoral immunity. Understanding how humoral immunity is maintained will shed light on strategies for the development of long term protective vaccination-induced antibody responses.